Department of Biology, College of Science and Health, University of Wisconsin-La Crosse, La Crosse, WI, USA.
Department of OBGYN, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.
Neurogastroenterol Motil. 2021 Apr;33(4):e14021. doi: 10.1111/nmo.14021. Epub 2020 Oct 28.
Stress increases intestinal secretion and exacerbates symptoms of irritable bowel syndrome (IBS). Peripherally derived corticotropin-releasing factor (CRF) is known to mediate stress-induced intestinal secretion, presumably by activation of CRF receptors in the gut. The present study aimed to ascertain the role of CRF activation in intestinal secretion by three other members of CRF peptide family, urocortin (UCN) 1-3, in wild type (WT) and CRF knockout (Crhr2 ) mice.
Mucosal/submucosal preparations from proximal colon of WT and Crhr2 mice of both sexes were mounted in Ussing chambers for measurement of short-circuit current (I ) as an indicator of ion secretion.
Male mice demonstrated a significantly higher baseline I than female in both WT and Crhr2 genotypes. CRF and UCN1-3 (1 μM) caused greater increases in colonic I (ΔI ) in male than female. Colonic I response to the selective CRF agonist, stressin1, was similar in both sexes. In male mice, the selective CRF agonists (UCN2 and UCN3) caused significantly greater ΔI than CRF and stressin1. UCN2- and UCN3-evoked ΔI was significantly reduced in preparations pretreated with the selective CRF antagonist antisauvagine-30 and in Crhr2 mice. The prosecretory effects of urocortins were due to increases in Cl secretion and involved enteric neurons and mast cells.
The findings revealed sex differences in baseline colonic secretion and responses to stress-related peptides. CRF receptors play a more prominent role in colonic secretion in male mice. The greater baseline secretion and responses to UCNs may contribute to the higher prevalence of diarrhea-predominant IBS in males.
压力会增加肠道分泌，加重肠易激综合征（IBS）的症状。已知外周来源的促肾上腺皮质释放因子（CRF）通过激活肠道中的 CRF 受体来介导应激诱导的肠道分泌。本研究旨在确定 CRF 肽家族的其他三个成员，即孤啡肽（UCN）1-3，在野生型（WT）和 CRF 敲除（Crhr2）小鼠中通过激活 CRF 受体在肠道分泌中的作用。
对 WT 和 Crhr2 两种性别的雄性和雌性小鼠的近端结肠黏膜/黏膜下组织进行 Ussing 室实验，以测量短电路电流（I）作为离子分泌的指标。
雄性小鼠的基础 I 值明显高于 WT 和 Crhr2 两种基因型的雌性小鼠。CRF 和 UCN1-3（1 μM）引起雄性小鼠的结肠 I （ΔI）增加大于雌性小鼠。两种性别对选择性 CRF 激动剂 stressin1 的结肠 I 反应相似。在雄性小鼠中，选择性 CRF 激动剂（UCN2 和 UCN3）引起的 ΔI 明显大于 CRF 和 stressin1。用选择性 CRF 拮抗剂 antisauvagine-30 预处理后，UCN2 和 UCN3 诱导的 ΔI 显著降低，且在 Crhr2 小鼠中也显著降低。孤啡肽引起的促分泌作用是由于 Cl 分泌增加，涉及肠神经元和肥大细胞。
研究结果揭示了基础结肠分泌和对应激相关肽反应的性别差异。CRF 受体在雄性小鼠的结肠分泌中发挥更重要的作用。较高的基础分泌和对 UCNs 的反应可能导致男性中腹泻为主的 IBS 更高的患病率。
